Chronic inflammation of the human intestine in Crohn’s disease (CD) causes bowel wall thickening, which typically progresses to stricturing and a recurrent need for surgery. Current therapies have limited success and CD remains idiopathic and incurable. Recent evidence shows a key role of intestinal smooth muscle cell (ISMC) hyperplasia in stricturing, which is not targeted by current anti-inflammatory therapeutics. However, progression of idiopathic pulmonary fibrosis, resembling CD in pathophysiology, is controlled by the tyrosine kinase inhibitors nintedanib (NIN) or pirfenidone, and we investigated these drugs for their effect on ISMC. In a culture model of rat ISMC, NIN inhibited serum- and PDGF-BB-stimulated growth and cell migration, and promoted the differentiated phenotype, while increasing secreted collagen. NIN did not affect signaling through PDGF-Rβ or NFκB but did inhibit cytokine-induced expression of the pro-inflammatory cytokines IL-1β and TNFα, supporting a transcriptional level of control. In TNBS-induced colitis in mice, which resembles CD, NIN decreased ISMC hyperplasia as well as expression of TNFα and IL-1β, without effect in control animals. NIN also inhibited growth of human ISMC in response to human serum or PDGF-BB, which further establishes a broad range of actions of NIN that support further trial in human IBD.
Background and PurposeNon‐erosive reflux disease (NERD) accounts for over half of all gastroesophageal reflux cases and is characterized by reflux symptoms with pathologic acid exposure on pH monitoring but no evidence of erosions on upper endoscopy. Ambulatory pH monitoring is limited by availability and patient tolerance. The utility of performing esophageal mucosal biopsies in diagnosing NERD is unclear. We conducted a systematic review and meta‐analysis to determine the sensitivity of esophageal mucosal biopsies in diagnosing NERD.MethodsData were obtained from Embase and Ovid MEDLINE from inception to April 2021. Studies were included if esophageal mucosal biopsies were taken and analyzed using conventional histopathologic analysis in symptomatic NERD patients. Relevant data was including histologic abnormalities and location of the biopsy. Sensitivity and specificity were calculated against healthy controls or those with functional heartburn.ResultsThe search yielded 2871 studies, of which 10 studies met our inclusion criteria and contained raw data. Histological abnormalities included histologic sum scores, papillary elongation, basal cell hyperplasia, and dilated intraepithelial spaces. When assessing for the presence of any abnormality, biopsies taken <3 cm from the lower esophageal sphincter (LES) had a pooled sensitivity of 0.71 (95% CI 0.64–0.77) and specificity of 0.64 (95% 0.54–0.73); however, analysis of individual histologic features such as the presence of eosinophils improved the sensitivity.ConclusionsAlthough esophageal mucosal biopsies had poor sensitivity at diagnosing NERD, biopsies taken within 3 cm of the LES had higher sensitivity when pathologists reported upon eosinophils and dilated intraepithelial spaces.
Background Chronic inflammation in inflammatory bowel disease (IBD) causes structural alterations of the intestine. In Crohn’s disease, this can lead to stricture formation, arising from unclear interactions among local inflammatory cells, cytokines, and mesenchymal intestinal cells. Specifically, proliferation of smooth muscle and increased deposition of collagen-rich extracellular matrix leads to fibrosis and obstructive wall thickening. Since there are minimal treatment options, we explored the effects of two multimodal tyrosine kinase inhibitors, nintedanib and pirfenidone, which were recently approved for idiopathic pulmonary fibrosis (IPF), a chronic lung condition resembling Crohn’s disease. Aims To understand the basic pharmacology of two novel anti-fibrotic tyrosine kinase inhibitors and their effects on cell proliferation and collagen deposition. Methods In vitro model systems of adult rat colonic circular smooth muscle cells (CSMS), rat IEC-18 intestinal epithelial cells or mouse 3T3 were assessed for response to serum or the mesenchymal growth factor PDGF-BB, evaluating growth responses by proliferation assay, and type I collagen expression by immunocytochemistry and western blotting. Programmed cell death was detected by ICC and western blotting for caspase-dependent apoptotic markers. Results Both 3T3 fibroblasts and rat ISMC showed concentration-dependent proliferation in response to serum or PDGF application. Nintedanib reduced this response to baseline at EC100 of 2.3 ± 0.7 (n=5) µM, and EC50 of 0.3 ± 0.1 (n=6) µM without cytotoxicity, while pirfenidone was ineffective at levels ≤ 5mM. Nintedanib (10 µM) was ineffective against serum-induced growth of rat IEC-18 cells while blocking growth of rat CSMC or mouse 3T3 fibroblasts in parallel assays, suggesting a selective effect on mesenchymal cell types. In nintedanib-treated cultures, nuclear staining showed concentration-dependent reduction of mitotic figures with proportional appearance of nuclear fragmentation, typical of apoptosis. Western blotting for collagen I identified at 125kD band for both CSMC and 3T3 cells and suggested down-regulation with both nintedanib and pirfenidone. Conclusions Novel anti-fibrotic therapies for chronic idiopathic pulmonary disease display distinctive effects on ISMC proliferation and extracellular matrix production. These address molecular mechanisms of fibrosis that are in common with IBD, and so the translation of therapeutic approaches may be a promising treatment option. Detecting specific mechanisms of action of nintedanib, such as apoptosis, leads to better targets for therapeutic options. Funding Agencies NSERC
Background Non-erosive reflux disease (NERD) accounts for over half of all cases of gastroesophageal reflux disease (GERD). It is characterized by symptoms of GERD with pathologic acid exposure on ambulatory pH monitoring and no evidence of erosive esophagitis on upper endoscopy. Symptoms and negative endoscopy alone are insufficient to diagnose NERD. Ambulatory pH monitoring is limited due to availability and patient tolerance. Conventional histologic analysis of mucosal esophageal biopsies has been studied in this context but there is no clear guidance as to its utility in diagnosing NERD. Aims The purpose of this study was to conduct a systematic review and meta-analysis to determine the sensitivity and specificity of esophageal biopsy histology in diagnosing NERD. Methods Data were obtained from Embase (1947- April 2021) and Ovid MEDLINE (1946 – April 2021). We included all studies where esophageal mucosal biopsies were taken and light microscopy was used to analyze histopathology in symptomatic adult NERD patients (i.e., no evidence of erosive esophagitis and ambulatory pH testing confirmed the presence of pathologic acid exposure). Papers were sorted in duplicate. Relevant data was extracted from papers meeting inclusion criteria, including histologic abnormalities and the location of the biopsy. Sensitivities and specificities were calculated from raw data and pooled using RevMan 5.4 software, using asymptomatic patients with no significant esophageal acid exposure and/or patients with functional heartburn (i.e., symptoms but no elevated acid exposure on ambulatory pH testing) as controls. Results The search yielded 2871 studies after the removal of duplicates, of which 158 were eligible for full text review. In total, 12 papers met our stringent inclusion criteria and contained raw data that allowed for sensitivity calculations. Histological abnormalities that were commonly reported included gross morphological scores, papillary elongation, basal cell hyperplasia and dilated intraepithelial spaces. Biopsies were taken at <3cm in 5 studies, ≥3cm in 5 studies, and at multiple sites in 2 studies, and all were reviewed by a blinded pathologist. When assessing for the presence of any abnormality in the histological analysis, biopsies taken at <3cm had a pooled sensitivity of 0.70 (95% CI 0.64 – 0.75) and specificity of 0.72 (95% CI 0.63 – 0.77). Biopsies taken at ≥3cm revealed a pooled sensitivity of 0.39 (95% CI 0.32 – 0.47) and specificity of 0.63 (95% CI 0.51 – 0.74). Conclusions Esophageal mucosal biopsies have poor sensitivity and specificity at diagnosing non-erosive gastroesophageal reflux disease. Biopsies taken below 3cm appear to have a higher sensitivity and specificity than those taken more proximally. Funding Agencies None
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